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Journal of Neurotrauma
J Neurotrauma. Mar 2009; 26(3): 325–331.
PMCID: PMC2752358
NIHMSID: NIHMS134399

Combination Therapy with Hypothermia for Treatment of Cerebral Ischemia

Abstract

Mild hypothermia is an established neuroprotectant in the laboratory, showing remarkable and consistent effects across multiple laboratories and models of brain injury. At the clinical level, mild hypothermia has shown benefits in patients who have suffered cardiac arrest and in some pediatric populations suffering hypoxic brain insults. However, a review of the literature has demonstrated that in order to appreciate the maximum benefits of hypothermia, brain cooling needs to begin soon after the insult, maintained for relatively long period periods of time, and, in the case of ischemic stroke, should be applied in conjunction with the re-establishment of cerebral perfusion. Translating this to the clinical arena can be challenging, especially rapid cooling and the re-establishment of perfusion. The addition of a second neuroprotectant could potentially (1) enhance overall protection, (2) prolong the temporal therapeutic window for hypothermia, or (3) provide protection where hypothermic treatment is only transient. Combination therapies resulting in recanalization following ischemic stroke would improve the likelihood of a good outcome, as the experimental literature suggests more consistent neuroprotection against ischemia with reperfusion, than ischemia without. Since recombinant tissue plasiminogen activator (rt-PA) is the only FDA approved treatment for acute ischemic stroke, and acts to recanalize occluded vessels, it is an obvious initial strategy to combine with hypothermia. However, the effects of thrombolytics are also temperature dependent, and the risk of hemorrhage is significant. The experimental data nevertheless seem to favor a combinatorial approach. Thus, in order to apply hypothermia to a broader range of patients, combination strategies should be further investigated.

Key words: hypothermia, neuroprotection, stroke, tissue plasminogen activator

Introduction

Hypothermia is a robust neuroprotectant and has consistently shown benefit against a variety of brain injuries at the experimental level. Hypothermia has often been viewed as the “gold standard” against which other laboratory data should be compared (Krieger and Yenari, 2004). In fact, therapeutic mild hypothermia is now being increasingly used by many centers in patients suffering cardiac arrest and coma. Although numerous pharmacological agents have been shown to be protective against experimental stroke, no clinical studies have convincingly shown benefit in humans. Clinical reports indicate that mild to moderate hypothermia can reduce brain edema due to stroke (Schwab et al., 2001), and body temperature is inversely correlated to infarct volume and clinical outcome (Reith et al., 1996).

A review of the experimental literature indicates that factors which affect the efficacy of hypothermia include the duration of cooling, the time when cooling begins, and reperfusion of the occluded vessel (Krieger and Yenari, 2004). Thus, longer periods of hypothermia instituted soon after the onset of ischemia are associated with better outcomes. However, it may not be possible to treat all stroke patients in this manner, and identifying ways in which combined therapies may enhance the likelihood of a positive result.

Optimal Conditions for Hypothermic Protection

Optimum conditions for hypothermic neuroprotection seem mostly affected by the duration and timing of cooling, rather than the depth of cooling. Improved neurological outcome is also more likely if the occluded vessel can be reperfused. While the mechanisms underlying the conditions by which hypothermia is protective (or not) are unknown, they should be taken into consideration when designing clinical trials. A more detailed knowledge of hypothermia's failings may also aid in strategic combinatorial approaches.

Depth and duration of cooling

Collective laboratory research has suggested that small decreases in temperature are as protective as larger decreases, and prolonging the duration of cooling may also permit more delayed application of hypothermia.

Different levels of hypothermia have been defined, depending on the depth of cooling: mild (>32°C), moderate (28–32°C), deep (20–28°C), profound (5–20°C), and ultraprofound (<5°C) hypothermia. Deep to ultraprofound hypothermia has been used extensively in the past for resuscitating trauma victims or during high-risk surgery such as cardiothoracic surgery requiring cardiac arrest or neurosurgery. Because of the numerous complications of deep to profound hypothermia and the difficulty in achieving and maintaining these temperatures, mild to moderate hypothermia are becoming more attractive alternatives (Lyden et al., 2006). Furthermore, experimental evidence, at least in focal cerebral ischemia models, indicates that the extent of neuroprotection is similar whether temperature is reduced to 34°C or 25°C (Kader et al., 1992; Maier et al., 1998; Huh et al., 2000).

The optimal duration of hypothermia after cerebral ischemic injury is unclear. Some groups have used brief durations of hypothermia (0.5–5 h), whereas others used longer periods (12–48 h), and neuroprotection was observed in nearly all cases (Krieger and Yenari, 2004). In a few studies of focal cerebral ischemia where the duration of hypothermia was compared directly, durations of 1–3 h appeared effective, whereas 0.5–1 h were not (Zhang et al., 1993; Maier et al., 1998). Longer durations may be necessary especially when the initiation of cooling is delayed, and this is corroborated by rodent data indicating robust neuroprotection when hypothermia is delayed by several hours, provided cooling is maintained for more than 24 h in both global (Colbourne et al., 1999) and focal (Colbourne et al., 2000) cerebral ischemia. In clinical stroke, hypothermia may be a more effective neuroprotective strategy if applied for a long duration after the ischemic event, as most patients do not present until hours after the onset of stroke (Carroll and Beek, 1992; Olsen et al., 2003). Although a long cooling time seems attractive, this may be offset by an increased risk of complications.

Timing of cooling

From laboratory studies, it is clear that cooling is remarkably neuroprotective when applied during ischemia. Therefore, hypothermia should be initiated as soon as possible to achieve its optimal beneficial effect. But because many patients do not present to the emergency room immediately after symptom onset, a critical question is how long after stroke can cooling be applied and still be effective. Rodent global cerebral ischemia models have been extensively studied in terms of delaying the initiation of cooling. Hypothermia commencing 30 min into the start of reperfusion was reported to be ineffective for protection of the hippocampal neurons (Busto et al., 1989), but in a gerbil forebrain ischemia model, hypothermia begun even 1 h after the start of reperfusion was reported to be effective if the hypothermia was continued for a long time (6 h) (Carroll and Beek, 1992). Yet, studies by a few groups (Dietrich et al., 1993; Shuaib et al., 1995) showed that post-ischemic hypothermia merely delayed the onset of irreversible neuronal injury, unless combined with a second neuroprotectant (Dietrich et al., 1995). However, this latter study only applied hypothermia for 3 h. More recent rodent experiments have shown that a prolonged reduction in temperature (12–48 h) of only a few degrees can provide sustained behavioral and histological neuroprotection as far as 6 months post-ischemia onset (Colbourne and Corbett, 1995; Colbourne et al., 1999). Thus, the extent of a neuroprotective effect is influenced by the length of the delay and the duration of hypothermia.

A few studies concerning the therapeutic time window in the focal cerebral ischemia model have been reported. In a study by Karibe et al. (1994), the therapeutic time window for obtaining a brain-protecting effect with mild hypothermia in the case of 2 h of middle cerebral artery occlusion (MCAO) was 10–30 min for the basal ganglia and 30–60 min for the cerebral cortex, and no reduction in the infarct volume was observed when mild hypothermia was begun 1 h after the start of ischemia. Baker et al.(1992) also reported that when hypothermia was begun within 1 h after the start of permanent MCAO (pMCAO), a reduction of the infarct volume was obtained after 24 h, but when mild hypothermia was begun at 2 h after the start of ischemia, no reduction of the infarct volume was observed. Yet other studies in models of temporary MCAO (tMCAO) indicate that delays of up to 3 h from the onset of ischemia with hypothermia maintained anywhere from 2 to 48 h is protective (Markarian et al., 1996; Colbourne et al., 2000; Maier et al., 2001). Rodents subjected to 2 h of MCAO can still benefit from hypothermia provided that cooling began within 3 h (Colbourne et al., 2000; Maier et al., 2001).

These studies collectively indicate that even delayed post-ischemic hypothermia can reduce the extent of ischemic injury due to focal cerebral ischemia, which is remarkably encouraging for clinicians. What parameters will be effective in humans remains to be determined, but in two clinical studies of therapeutic mild hypothermia in cardiac arrest patients showed neurologic efficacy when cooling began within 2 h of the return of circulation and maintained for 12–24 h (Bernard et al., 2002; Hypothermia after Cardiac Arrest Study Group, 2002). A few pilot studies in ischemic stroke patients have been published indicating feasibility, though efficacy remains to be established (Lyden et al., 2006, Hemmen and Lyden, 2007).

Is protection long term?

As mentioned above, prior work showed only transient protective effects of hypothermia in the global cerebral ischemia model when cooling began during reperfusion and maintained for 3 h (Dietrich et al., 1993; Shuaib et al., 1995). However, long-term protection has been documented in several studies. Following global cerebral ischemia, hypothermic protection was sustained out to 6 months provided cooling was maintained for 24 h (Colbourne and Corbett, 1995), but the effect was not as robust as at 1 month. In a model of tMCAO, intraischemic hypothermia for 2 h resulted in protection that was sustained up to 2 months (Maier et al., 2001). Similar results in focal cerebral ischemia were reported by Corbett et al (Corbett et al., 2000), but in this case cooling was delayed by 1 h and maintained for 2 days. Thus, long-term protection can be attained for relatively short durations of cooling provided cooling begins immediately after ischemia onset, or cooling can be delayed but the duration of cooling must be prolonged.

Is recanalization important?: Temporary versus permanent middle cerebral artery occlusion studies

Although laboratory studies have shown consistent protection by hypothermia against temporary ischemia, data from permanent ischemia models are less consistent. Using a rat pMCAO model, Baker et al. (1991) found that 6 h of intraischemic deep hypothermia (24°C) showed remarkable protection when brains were assessed at 6 h post-ischemia. Prolonged cooling was also neuroprotective. Yanamoto et al. (2001) applied mild (33°C) and moderate (30°C) hypothermia for 24 h immediately after ischemia onset in a rat permanent focal ischemia model, and found reduced infarct volume and improved behavioral outcome as far out as 21 days. When cooling was delayed 1 h after ischemia onset and maintained for 1 h, infarct volume was reduced compared to the normothermic animals (Kader et al., 1992). However, in another study, mild hypothermia started after 2 h of pMCAO and maintained for 2 h was not protective; while moderate hypothermia was protective and even more effective than prolonged mild hypothermia (2 h intraischemic hypothermia plus another consecutive 2 h) (Zhao et al., 2007). Other studies have also reported that hypothermia does not protect against permanent ischemia. Ridenour et al. (1992) compared the effects of mild hypothermia against permanent and temporary MCAO in the rat model. Two-hour hypothermia initiated right after ischemia did not show any protection against pMCAO, but did protect against 1-h tMCAO at 24 h. Similar findings were also reported by another group (Morikawa et al., 1992). Reasons for these conflicting results are many, but could reflect the different duration of cooling, and more importantly underscores the possibility that hypothermia is less effective, or less consistently effective against pMCAO than tMCAO. These findings have obvious implications at the clinical level where recanalization often does not spontaneously occur, but requires therapeutic recanalization with pharmacologic or mechanical approaches.

Summary

Optimal conditions for this therapy based on preclinical studies include temperatures of 34.5°C or lower, cooling should be sustained for at least one hour, provided cooling begins soon after ischemia onset. Hypothermia should be maintained for at least 6–12 h if cooling is delayed by more than several hours. Hypothermia with a delay of up to 6 h is still effective provided cooling is maintained for 1–2 days. Long-term protection has been observed up to 2 months with 2-h intraischemic cooling, or 1-h delay with prolonged cooling (2 days) in focal models. Long-term protection has been documented in the global model out to 6 months provided cooling is maintained for 24 h, but the extent of protection decreases over time. For permanent occlusion, results varied widely, but protection can be seen if cooling begins before or immediately after ischemia onset, and if cooling is prolonged (>12 h). Brief intraischemic hypothermia (1–2 h) protects, but also protects when cooling begins 2–3 h after ischemia onset. Delayed cooling may result in the loss of long-term protection, if cooling period is short (documented in global, but not focal ischemia). Prolonging the duration of cooling to several hours seems to lengthen the temporal therapeutic window, and allow for sustained protection (better documented in global models).

Hypothermia in Combination with Other Neuroprotectants

As demonstrated above, hypothermia is a robust neuroprotectant, and part of this may be due to the fact that it appears to protect by multiple mechanisms, rather than by a single mechanism which is what most pharmaceutical agents aim to do (Gupta et al., 2005). However, therapeutic hypothermia still has its limitations, and some may not be easily overcome at the clinical level. For example, it is clear that cooling should be initiated as soon after ischemia onset as possible and maintained for longer periods of time. Early reperfusion is also preferable to no or late reperfusion. However, many patients do not present soon after a stroke has occurred, and the vast majority of patients do not meet criteria for treatment with tissue plasminogen activator (rt-PA) or mechanical thrombectomy. Thus, it would make cogent sense to combine therapeutic approaches to enhance the chances of a favorable outcome or provide protection where protection is less likely by hypothermia. In fact, it is well known now by many researchers that many clinical studies of neuroprotectants have failed for various reasons. However, many now realize that neuroprotection may be attainable if multiple treatments could be given to act synergistically (Wahlgren and Lyden, 2000; Rogalewski et al., 2006; Ginsberg, 2008). Hypothermia is certainly no exception to this concept. Here we review how hypothermia may be combined with other therapeutic strategies.

In general, three approaches could be considered to enhance the changes of hypothermic neuroprotection. The first is a “kitchen sink” approach where multiple therapies are instituted at once with the hope that if each therapy is effective on its own; they should be even better together. A second approach may be to identify situations where hypothermia is less likely to be effective (e.g., delayed cooling) and combine it with another neuroprotective strategy to increase the likelihood of a positive result. A third approach should take into consideration the preclinical data showing that, while long-term protection by hypothermia is possible, the degree of protection is lost as time goes by. Thus, it is important to identify strategies to prevent losses in any protective effect over time. Finally, it should be emphasized that hypothermia works better and more consistently in experimental focal ischemia if the occluding vessel is reperfused. Since rt-PA and the MERCI retriever device (Smith et al., 2008) are approved therapies for recanalizing occluded cerebral vessels, an obvious question is whether these treatment could be combined at the clinical level.

Combination therapy for synergy

Clearly, one would assume that if two different neuroprotective strategies worked separately, then both should work better if combined. A few preclinical studies have shown this to be the case where combining an effective pharmacological approach with hypothermia results in an outcome superior to either treatment alone. The synergistic effect of combination therapy was profoundly demonstrated by the combination of magnesium, tirilazad, and hypothermia (MTH). In a rat tMCAO model, tirilazad and MgCl2 were given in two doses, one before ischemia and the second after reperfusion. Together with mild hypothermia, this trio of therapies significantly reduced the infarct by 77%, while tirilazad and MgCl2 treatment alone reduced infarct size by 56% and the hypothermia alone reduced it by 63% (Schmid-Elsaesser et al., 1999). Furthermore, the administration of tirilazad and MgCl2 could be delayed. The latest time for tirilazad and MgCl2 in combination with intraischemic hypothermia was 3 h after ischemia onset (Zausinger et al., 2003). MTH therapy was even effective in a rat pMCAO model, with significantly improved neurological function at 7 days (Scholler et al., 2004).

Another combination strategy is that of caffeine and ethanol, or caffeinol. Prior work has shown salutary effects of the combination of caffeine and ethanol in rodent stroke models, but either therapy alone was ineffective. When caffeinol was paired with intraischemic hypothermia in a model of 3-h tMCAO, treatment with caffeinol began 4 h after after ischemia onset, while cooling to 35°C for 4 h began at the same time. Investigators showed that both hypothermia and caffeinol reduced infarct size to similar extents (~50%), the addition of hypothermia further reduced infarct size by another ~60% (Aronowski et al., 2003). A clinical study of combination therapy with hypothermia, rt-PA and caffeinol is ongoing, and is perhaps the first clinical combination study of hypothermia and a pharmacological neuroprotectant in stroke patients. Preliminary observations in 20 patients indicate that this approach is feasible (Martin-Schild et al., 2008).

Similar results were reported when hypothermia was combined with the trophic factor, brain-derived neurotrophic factor (BDNF) (Berger et al., 2004) or the spin trap agent N-tert-butyl-alpha-pheylnitrone (PBN) (Pazos et al., 1999). However, other studies using combinations of minocycline (Wang et al., 2002, 2003; Nagel et al., 2008), N-acetyl-aspartyl-glutamate (NAAG [Van Hemelrijck et al., 2005]), or hypertention with mannitol (Ogilvy et al., 1996) failed to show synergistic effects of combinatorial approaches with hypothermia. An older study of multiple potentially therapeutic combinations of moderate hypothermia with dexamethasone, hypertension, hemodilution and barbiturates in a model of global ischemia in monkeys also failed to show significant improvement compared to no intervention (Gisvold et al., 1984). Lack of synergy in some studies may be due to the robust effect of hypothermia and/or the second neuroprotectant in the model studied. Thus, a “ceiling effect” may have been reached, and no further protection could be demonstrated.

Hypothermia to extend the temporal therapeutic window for other neuroprotectants

A critical problem with translating therapies from the lab into humans is the time from symptom onset when treatment can be administered. This is because most neuroprotectants, if they are going to work, need to be given soon after the onset of ischemia, or even before ischemia onset. However, the majority of stroke patients do not present for medical care until hours or even days later. This fact is borne out by post approval studies of rt-PA where less than 5% of all stroke patients are treated with it (Reed et al., 2001). Thus, one approach to extending the time window for potential neuroprotectants is to initiate cooling immediately—possibly in the field, as was done in one of the cardiac arrest studies (Hypothermia after Cardiac Arrest Study Group, 2002), followed by treatment with a second neuroprotectant.

One example of this strategy can be demonstrated for the use of gene therapy. Our research group showed that Bcl-2, an anti-apoptotic gene, protects ischemic neurons when delayed 1.5 h post-MCAO, but not if delayed 5 h after MCAO (Lawrence et al., 1997). Combination therapy could extend the temporal therapeutic window of Bcl-2 gene transfer from 1.5 to 5 h if hypothermia (33°C) was initiated immediately after reperfusion and maintained for 3 h (Zhao et al., 2004). Similar effects have been reported for FK506 (Tacrolimus). The temporal therapeutic window for FK506 treatment in brain ischemia was estimated to be greater than 1 h, but less than 2 h. Combining treatment with hypothermia led to an expansion of the temporal therapeutic window to 2 h (Nito et al., 2004).

However, most pharmacologic neuroprotectants may be easier to administer in the field than it is to cool a patient. Thus, it would make sense to pursue studies to see if potential pharmacological neuroprotectants might expand the temporal therapeutic window for hypothermic protection. Yet, no such studies appear to have been published to date. One exception is where hypothermia might be used in combination with thrombolysis discussed below.

Combination therapy with hypothermia to sustain protection

Combination treatment of a neuroprotectant with hypothermia can also sustain protection, where hypothermic protection was previously found to be only transient. Studies have shown that post ischemic hypothermic protection with cooling for 3 h is transient following forebrain ischemia (Dietrich et al., 1993; Shuaib et al., 1995). However, if hypothermia is followed by the injection of the NMDA antagonist MK-801 on postischemic days 3, 5, and 7, animals showed long-lasting neurobehavioral protection out to 6–8 weeks (Green et al., 1995). Further, mild hypothermia (33–34°C immediately upon reperfusion for 4 h) combined with anti-inflammatory cytokine IL-10 given in the immediate postischemic period, as well as 3 days after ischemia, histologic protection in hippocampal CA1 could last up to 2 months (Dietrich et al., 1999). Similarly, anti-inflammatory treatment with dipyrone prevented the long-term loss of protection by hypothermia possibly by preventing post ischemic hyperthermia (Coimbra et al., 1996).

Hypothermia and rt-PA

An obvious combinatorial approach with hypothermia is that with fibrinolysis, since rt-PA is the only approved and effective method of recanalizing occluded cerebral vessels acutely. Furthermore, collective preclinical data indicate that hypothermia is more consistently effective when there is reperfusion of the occluded vessel. But before addressing the question of synergy, the safety of combining hypothermia with rt-PA should also be considered. Fatal hemorrhage is the most feared complication of fibrinolytic use, and fibrinolytic systems, being a cascade of temperature dependent enzymes, are most certainly affected by hypothermia. In an early study, we found that, in an in vitro system, clot lysis was temperature dependent (Yenari et al., 1995). When suspension of thrombi were incubated at various temperatures between 24–40°C, spontaneous clot lysis increased by 0.5% for each 1-°C drop in temperature. When rt-PA was added to clot suspensions, a 1-°C drop in temperature actually decreased clot lysis by a similar amount. While this study was conducted in vitro, and changes in clot lysis were relatively small, it underscores the need to carefully study this combination at the preclinical level before bringing such a trial into humans.

Preliminary work from our lab suggests that the combination should at least be safe. We launched a project in order to further address this issue (Liu et al., 2006). In this study, mice subjected to 2-h MCAO using an intraluminal suture, and were given rt-PA 3 h after ischemia onset. Rt-PA increased cerebral hemorrhage among normothermic animals, but hemorrhage scores among hypothermic rt-PA treated and normothermic ischemic mice were similar. Further, mice receiving mild hypothermia in combination with rt-PA had smaller infarcts than normothermic mice not given rt-PA and mice receiving rt-PA at normothermia.

In models of embolic stroke, which are more appropriate to directly testing efficacy of thrombolytics, it is not clear if hypothermia and rt-PA is synergistic. Two different studies essentially support a lack of synergy between the two treatment modalities. Using a rat embolic model, Meden et al. (1994) showed that, at 2 h after embolization, rt-PA could significantly reduce the infarct volume. Three-hour hypothermia (32°C) begun immediately after embolization reduced the infarct volume even more remarkedly. However, the combination of hypothermia and rt-PA treatment did not show further protection. These investigators also performed angiograms and found that improved recanalization was best seen in hyperthermic animals, and similar recanalization was observed at normothermia and hypothermia. In another similar study, using a rat ischemia model by thromboembolic occlusion of middle cerebral artery, rt-PA was given 1 or 3 h after embolization, and cooling (33°C) was started 1 h after embolization and maintained for 4 h. Infarct size was assessed with MRI. The results showed that animals receiving rt-PA all had better recovery of cerebral perfusion. However, animals in all hypothermic groups had less injury, regardless of whether they received rt-PA. Combination of rt-PA and hypothermia also did not show further improvement (Kollmar et al., 2004).

Combination therapy of hypothermia to expand the therapeutic window of thrombolytic use should certainly be explored. Treatment with rt-PA or the MERCI clot retrieving device cannot be easily or safely implemented in the field, and both are only approved for relatively short time windows where therapy can be initiated. Thus, hypothermia could be initiated in the field while patients are transported to centers for therapeutic recanalization. While still a concept for future thought, clinical studies of hypothermia and rt-PA are ongoing (Lyden et al., 2005; Guluma et al., 2006).

Conclusion

Hypothermia is a robust protestant against brain ischemia and trauma. Its effect is especially related to the duration and timing of cooling. Limitations may include variable efficacy against permanent ischemia (especially when delayed); delayed cooling in forebrain ischemia; and the need for prolonged cooling. Hypothermia in combination with other protectants can be synergistic. Combination therapy with hypothermia can be strategically applied to protect where hypothermia falls or a second neuroprotection falls short. It is less clear whether combination therapy with hypothermia and rt-PA provide synergistic protection. Limited data at least suggest that the combination might be safe.

Acknowledgments

This work was supported by NIH NINDS (grants R01 NS40516, P50 NS014543, and P01 NS37520, all to M.A.Y.) and the American Heart Association Established Investigator Award (to M.A.Y.).

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